Enhanced brain amyloid-β clearance by rifampicin and caffeine as a possible protective mechanism against Alzheimer's disease.
Rifampicin and caffeine are widely used drugs with reported protective effect against Alzheimer's disease (AD). However, the mechanism underlying this effect is incompletely understood. In this study, we have hypothesized that enhanced amyloid-β (Aβ) clearance from the brain across the blood-brain barrier (BBB) of wild-type mice treated with rifampicin or caffeine is caused by both drugs potential to upregulate low-density lipoprotein receptor related protein-1 (LRP1) and/or P-glycoprotein (P-gp) at the BBB. Expression studies of LRP1 and P-gp in brain endothelial cells and isolated mice brain microvessels following treatment with rifampicin or caffeine demonstrated both drugs as P-gp inducers, and only rifampicin as an LRP1 inducer. Also, brain efflux index (BEI%) studies conducted on C57BL/6 mice treated with either drug to study alterations in Aβ clearance demonstrated the BEI% of Aβ in rifampicin (82.4 ± 4.3%) and caffeine (80.4 ± 4.8%) treated mice were significantly higher than those of control mice (62.4 ± 6.1%, p < 0.01). LRP1 and P-gp inhibition studies confirmed the importance of both proteins to the clearance of Aβ, and that enhanced clearance following drugs treatment was caused by LRP1 and/or P-gp upregulation at the mouse BBB. Furthermore, our results provided evidence for the presence of a yet to be identified transporter/receptor that plays significant role in Aβ clearance and is upregulated by caffeine and rifampicin. In conclusion, our results demonstrated the upregulation of LRP1 and P-gp at the BBB by rifampicin and caffeine enhanced brain Aβ clearance, and this effect could explain, at least in part, the protective effect of rifampicin and caffeine against AD.


Staying home to give birth: why women in the United States choose home birth.
Approximately 1% of American women give birth at home and face substantial obstacles when they make this choice. This study describes the reasons that women in the United States choose home birth. A qualitative descriptive secondary analysis was conducted in a previously collected dataset obtained via an online survey. The sample consisted of 160 women who were US residents and planned a home birth at least once. Content analysis was used to study the responses from women to one essay question: "Why did you choose home birth?" Women who participated in the study were mostly married (91%) and white (87%). The majority (62%) had a college education. Our analysis revealed 508 separate statements about why these women chose home birth. Responses were coded and categorized into 26 common themes. The most common reasons given for wanting to birth at home were: 1) safety (n = 38); 2) avoidance of unnecessary medical interventions common in hospital births (n = 38); 3) previous negative hospital experience (n = 37); 4) more control (n = 35); and 5) comfortable, familiar environment (n = 30). Another dominant theme was women's trust in the birth process (n = 25). Women equated medical intervention with reduced safety and trusted their bodies' inherent ability to give birth without interference.


Shape of the Recorded Area in Precession Photographs and Its Application in Orienting Crystals.
The equation of the perimeter of the recorded area of zero-level precession photographs as a function of the orientation error is derived in polar coordinates. The angle between the tangent to the perimeter and the radius vector is also derived. How these relations can be conveniently applied to determining the orientation error of a crystal mounted on the precession instrument is discussed.


A genomic analysis of transcytosis in the pea aphid, Acyrthosiphon pisum, a mechanism involved in virus transmission.
Aphids are the primary vectors of plant viruses. Transmission can occur via attachment to the cuticle lining of the insect (non-circulative transmission) or after internalization in the insect cells with or without replication (circulative transmission). In this paper, we have focused on the circulative and non-propagative mode during which virions enter the cell following receptor-mediated endocytosis, are transported across the cell in vesicles and released by exocytosis without replicating. The correct uptake, transport and delivery of the vesicles cargo relies on the participation of proteins from different families which have been identified in the Acyrthosiphon pisum genome. Assemblage of this annotated dataset provides a useful basis to improve our understanding of the molecules and mechanisms involved in virus transmission by A. pisum and other aphid species.


Long-term outcomes in antimitochondrial antibody negative primary biliary cirrhosis.
Antimitochondrial antibodies (AMA) are a sensitive and specific marker for primary biliary cirrhosis (PBC). AMAs are present in 95% of patients with PBC. However, 5% do not have AMAs and data on these patients is scarce. We aim to evaluate the long-term outcomes of patients with AMA negative PBC. A retrospective chart review of 71 AMA negative PBC patients. Disease presentation, laboratory results, and clinical endpoints were recorded. AMA negative patients were matched on year of diagnosis to a control group of 71 AMA positive patients. Ninety-six percent of the AMA negative patients were of female gender with a median age at diagnosis of 55 years and a length of follow-up of 7.5 years vs. 86% females, a median age of 56 and a follow-up of 8.3 years in the control group. Mean total bilirubin and alkaline phosphatase levels were 0.7 mg/dL vs. 0.6 and 570 U/L vs 341, in AMA negative vs. AMA positive patients at presentation, respectively (p = NS). AMA negative patients did not differ in terms of age, serum IgM levels, ANA status, or length of follow-up. Notably, AMA negative patients had a significantly reduced survival free of liver-related complications including transplantation and death compared to AMA positive patients (p = 0.0182). In this large experience, AMA negative PBC patients had a significantly worse prognosis compared to AMA positive PBC patients. The reason for the difference in prognosis is unclear, as it may be true difference or reflect delays in case detection among AMA negative patients.


Single-agent bortezomib in previously untreated multiple myeloma: efficacy, characterization of peripheral neuropathy, and molecular correlations with response and neuropathy.
PURPOSE To assess efficacy and safety of single-agent bortezomib in previously untreated patients with multiple myeloma, investigate prevalence of baseline and treatment-emergent polyneuropathy, and identify molecular markers associated with response and neuropathy. PATIENTS AND METHODS Patients received bortezomib 1.3 mg/m(2) on days 1, 4, 8, and 11, for up to eight 21-day cycles. A subset of patients underwent neurophysiologic evaluation pre- and post-treatment. Bone marrow aspirates were performed at baseline for exploratory whole-genome analyses. Results Among 64 patients, 41% had partial response or better, including 9% complete/near-complete responses; median duration of response was 8.4 months. Response rates did not differ in the presence or absence of adverse cytogenetics. After median follow-up of 29 months, median time to progression was 17.3 months. Median overall survival had not been reached; estimated 1-year survival was 92%. Thirty-two patients successfully underwent optional stem-cell transplantation. Bortezomib treatment was generally well tolerated. At baseline, 20% of patients had sensory polyneuropathy. Sensory polyneuropathy developed during treatment in 64% of patients (grade 3 in 3%), but proved manageable and resolved in 85% within a median of 98 days. Neurologic examination, neurophysiologic testing, and measurements of epidermal nerve fiber densities in 35 patients confirmed pretreatment sensory neuropathy in 20% and new or worsening neuropathy in 63%. Pharmacogenomic analyses identified molecular markers of response and treatment-emergent neuropathy, which will require future study. CONCLUSION Single-agent bortezomib is effective in previously untreated myeloma. Baseline myeloma-associated neuropathy seems more common than previously reported, and bortezomib-associated neuropathy, although a common toxicity, is reversible in most patients.


A truncated HIV-1 Tat protein basic domain rapidly translocates through the plasma membrane and accumulates in the cell nucleus.
Tat is an 86-amino acid protein involved in the replication of human immunodeficiency virus type 1 (HIV-1). Several studies have shown that exogenous Tat protein was able to translocate through the plasma membrane and to reach the nucleus to transactivate the viral genome. A region of the Tat protein centered on a cluster of basic amino acids has been assigned to this translocation activity. Recent data have demonstrated that chemical coupling of a Tat-derived peptide (extending from residues 37 to 72) to several proteins allowed their functional internalization into several cell lines or tissues. A part of this same domain can be folded in an alpha-helix structure with amphipathic characteristics. Such helical structures have been considered as key determinants for the uptake of several enveloped viruses by fusion or endocytosis. In the present study, we have delineated the main determinants required for Tat translocation within this sequence by synthesizing several peptides covering the Tat domain from residues 37 to 60. Unexpectedly, the domain extending from amino acid 37 to 47, which corresponds to the alpha-helix structure, is not required for cellular uptake and for nuclear translocation. Peptide internalization was assessed by direct labeling with fluorescein or by indirect immunofluorescence using a monoclonal antibody directed against the Tat basic cluster. Both approaches established that all peptides containing the basic domain are taken up by cells within less than 5 min at concentrations as low as 100 nM. In contrast, a peptide with a full alpha-helix but with a truncated basic amino acid cluster is not taken up by cells. The internalization process does not involve an endocytic pathway, as no inhibition of the uptake was observed at 4 degrees C. Similar observations have been reported for a basic amino acid-rich peptide derived from the Antennapedia homeodomain (1). Short peptides allowing efficient translocation through the plasma membrane could be useful vectors for the intracellular delivery of various non-permeant drugs including antisense oligonucleotides and peptides of pharmacological interest.


Outcome Preferences in Patients With Noninfectious Uveitis: Results of a Best-Worst Scaling Study.
To estimate patient preferences regarding potential adverse outcomes of local versus systemic corticosteroid therapies for noninfectious uveitis by using a best-worst scaling (BWS) approach. Local and systemic therapies are alternatives for noninfectious uveitis that have different potential adverse outcomes. Patients participating in the Multicenter Uveitis Steroid Treatment Trial Follow-up Study (MUST FS) and additional patients with a history of noninfectious uveitis treated at two academic medical centers (Johns Hopkins University and University of Pennsylvania) were surveyed about their preferences regarding six adverse outcomes deemed important to patients. Using "case 1" BWS, patients were asked to repeatedly select the most and least worrying from a list of outcomes (in the survey three outcomes per task). Eighty-two patients in the MUST FS and 100 patients treated at the academic medical centers completed the survey. According to BWS, patients were more likely to select vision not meeting the requirement for driving (individual BWS score: median = 3, interquartile range, 0-5), development of glaucoma (2, 1-4), and needing eye surgery (1, 0-3) as the most worrying outcomes as compared to needing medicine for high blood pressure/cholesterol (-2, -4 to 0), development of cataracts (-2, -3 to -1), or infection (sinusitis) (-3, -5 to 0). Larger BWS scores indicated the outcomes were more worrying to patients. Patients with noninfectious uveitis considered impaired vision, development of glaucoma, and need for eye surgery worrying adverse outcomes, which suggests that it is especially desirable to avoid these outcomes if possible. (ClinicalTrials.gov number, NCT00132691.)


Bone Marrow and Muscle Fat Infiltration Are Correlated among Postmenopausal Women With Osteoporosis: The AMBERS Cohort Study.
Bone and muscle have shown to interact, but little is known about fat within bone and muscle. Clinical studies have isolated fat within bone and muscle using MRI. In this cross-sectional study, we hypothesized that bone marrow adiposity and muscle adiposity are related and that this relationship is associated with osteoporosis. Postmenopausal women aged 60 to 85 years were recruited as part of the Appendicular Muscle and Bone Extension Research Study (AMBERS). Participants completed dual-energy X-ray absorptiometry (DXA) of the hip and spine to diagnose osteoporosis. Muscle adiposity was measured with MRI at the 66% site of the leg. Fat segmentation was achieved using a semi-automated iterative threshold-optimizing algorithm (error < 5%). Peripheral quantitative computed tomography measured marrow density of the 4% distal tibia (surrogate for marrow fat) by threshold-based, edge-detection segmentations and by examining residuals from trabecular bone density regressed on trabecular tissue mineral density. Muscle adiposity from MRI was regressed on marrow density using linear regression. Models were further examined with an interaction with osteoporosis status. Among 312 women (aged 75.4 ± 5.9 years, body mass index [BMI] 29.5 ± 5.7 kg/m2 ), a larger amount of muscle fat was associated with lower marrow density at the 66% mid-tibia (B = 84.08 [27.56], p = 0.002) and at the 4% distal tibia (B = 129.17 [55.96], p = 0.022) after accounting for age, height, weight, average daily energy expenditure, hypertension, and diabetes. Interactions of this relationship with osteoporosis status were also significant. Upon probing these interactions, the relationships were significant only in women with osteoporosis but not in those without osteoporosis. Fat from bone marrow and muscle may be related to one another through the same phenomenon, which is likely also responsible for osteoporosis, but independent of hypertension and diabetes. More research should focus on the potential abnormalities in muscle and bone fat metabolism and mesenchymal cell commitment to fat within patients with osteoporosis. © 2019 American Society for Bone and Mineral Research.


Pharmaceutical microparticle engineering with electrospraying: the role of mixed solvent systems in particle formation and characteristics.
Microparticles of Celecoxib, dispersed in a matrix of poly(lactic-co-glycolic acid) (PLGA), were prepared by electrospraying using different solvent mixtures to investigate the influence upon particle formation and the resulting particle characteristics. Mixtures consisting of a good solvent, acetone, and an anti-solvent, methanol, for PLGA were studied in different ratios. Properties of the spraying solutions were examined and the resulting microparticles were characterized with regard to size, morphology, porosity, solid state form, surface chemistry and drug release. Particle formation was strongly influenced by the polymer molecular conformation during droplet formation and by the anti-solvent concentration during droplet drying. A strong correlation was found between particle morphology and the solubility of the polymer in the solvent mixtures. The lack of chain entanglements in droplets containing anti-solvent resulted in compact polymer conformation and grain-like particle morphology. Further, the early precipitation of polymer and low chain interaction with increasing content of anti-solvent resulted in surface enrichment of drug (from 10 and 20% up to 41 and 57% respectively), also demonstrated by the increasingly higher drug release rates. The results demonstrate the importance of solvent composition in particle preparation and indicate potential for exploiting this dependence to improve pharmaceutical particle design and performance.


A 33-yr follow-up of peak oxygen uptake and related variables of former physical education students.
In 1949, 27 female and 26 male physical education students were studied at a mean age of 22 and 25 yr, respectively. They were restudied in 1970 and 1982. Measurements included oxygen uptake, heart rate, and pulmonary ventilation during submaximal and maximal exercise on a cycle ergometer and treadmill. After 21 yr, peak aerobic power was significantly reduced, from 2.90 to 2.18 l/min and from 4.09 to 3.28 l/min for women and men, respectively. After another 12 yr, the 1970 maxima were not reduced further. From 1949 to 1982 there was a decrease in peak heart rate from 196 to 177 beats/min in women and from 190 to 175 beats/min in men (P < 0.05). Highest pulmonary ventilation did not change significantly. At an oxygen uptake of 1.5 l/min, the heart rate was the same in 1949 as in 1982. In conclusion, the physical fitness level of the subjects was well above average for these ages. From 1970 to 1982 there was no decline in the average peak aerobic power, a finding possibly related to increased habitual physical activity.


Hygienic and health characteristics of donkey milk during a follow-up study.
For its characteristics, donkey milk has been proposed as an alternative to goat or artificial milk to feed allergic infants. Therefore, it is important to increase our knowledge on health and immunological characteristics of donkey milk. Ten donkeys, bred as companion animals, were enrolled in this study and sampled once a month, for eight months. Milk (10 ml) was collected from each half udder for somatic cell count (SCC), bacteriological analysis and total bacteria count (TBC). The major pathogens were tested for antimicrobial susceptibility, and Staphylococcus aureus isolates were further genotyped by nanoarray analysis. Whey lysozyme and NAGase (NAG) activities were also assessed. Overall, 101 half-udder milk samples were taken. They showed very low values of TBC (<250 cfu/ml) and SCC (<50 000 cells/ml) and a minor prevalence of pathogens: Staph. aureus was isolated only from 5 milk samples (3 animals), Streptococcus equi from 2 samples and Str. equisimilis from a single sample. All the isolates were sensitive to all antibiotic classes used in veterinary medicine. None of the Staph. aureus isolates were shown to harbour genes coding for any enterotoxin, toxic-shock syndrome toxin or antibiotic resistance. Lysozyme levels were always very high (4000-5000 U/ml), while NAG values were mostly low (<50 U/ml), out of the last part of lactation. The results of this study confirmed the low prevalence of intramammary infections in donkey and the absence of food-borne pathogens, suggesting that donkey milk could be a safe food, if the mammary gland is healthy and the animals are milked in proper hygienic conditions.


Computational modelling of solvent effects in a prolific solvatomorphic porous organic cage.
Crystal structure prediction methods can enable the in silico design of functional molecular crystals, but solvent effects can have a major influence on relative lattice energies, sometimes thwarting predictions. This is particularly true for porous solids, where solvent included in the pores can have an important energetic contribution. We present a Monte Carlo solvent insertion procedure for predicting the solvent filling of porous structures from crystal structure prediction landscapes, tested using a highly solvatomorphic porous organic cage molecule, CC1. Using this method, we can understand why the predicted global energy minimum structure for CC1 is never observed from solvent crystallisation. We also explain the formation of three different solvatomorphs of CC1 from three structurally-similar chlorinated solvents. Calculated solvent stabilisation energies are found to correlate with experimental results from thermogravimetric analysis, suggesting a future computational framework for a priori materials design that factors in solvation effects.


Identification of protein targets of 4-hydroxynonenal using click chemistry for ex vivo biotinylation of azido and alkynyl derivatives.
Polyunsaturated fatty acids (PUFA) are primary targets of free radical damage during oxidative stress. Diffusible electrophilic alpha,beta-unsaturated aldehydes, such as 4-hydroxynonenal (HNE), have been shown to modify proteins that mediate cell signaling (e.g., IKK and Keap1) and alter gene expression pathways responsible for inducing antioxidant genes, heat shock proteins, and the DNA damage response. To fully understand cellular responses to HNE, it is important to determine its protein targets in an unbiased fashion. This requires a strategy for detecting and isolating HNE-modified proteins regardless of the nature of the chemical linkage between HNE and its targets. Azido or alkynyl derivatives of HNE were synthesized and demonstrated to be equivalent to HNE in their ability to induce heme oxygenase induction and induce apoptosis in colon cancer (RKO) cells. Cells exposed to the tagged HNE derivatives were lysed and exposed to reagents to effect Staudinger ligation or copper-catalyzed Huisgen 1,3 dipolar cycloaddition reaction (click chemistry) to conjugate HNE-adducted proteins with biotin for subsequent affinity purification. Both strategies yielded efficient biotinylation of tagged HNE-protein conjugates, but click chemistry was found to be superior for the recovery of biotinylated proteins from streptavidin-coated beads. Biotinylated proteins were detected in lysates from RKO cell incubations with azido-HNE at concentrations as low as 1 microM. These proteins were affinity purified with streptavidin beads, and proteomic analysis was performed by linear ion trap mass spectrometry. Proteomic analysis revealed a dose-dependent increase in labeled proteins with increased sequence coverage at higher concentrations. Several proteins involved in stress signaling (heat shock proteins 70 and 90 and the 78-kDa glucose-regulated protein) were selectively adducted by azido- and alkynyl-HNE. The use of azido and alkynyl derivatives in conjunction with click chemistry appears to be a valuable approach for the identification of the protein targets of HNE.


Indigenous well-being in four countries: an application of the UNDP'S human development index to indigenous peoples in Australia, Canada, New Zealand, and the United States.
Canada, the United States, Australia, and New Zealand consistently place near the top of the United Nations Development Programme's Human Development Index (HDI) rankings, yet all have minority Indigenous populations with much poorer health and social conditions than non-Indigenous peoples. It is unclear just how the socioeconomic and health status of Indigenous peoples in these countries has changed in recent decades, and it remains generally unknown whether the overall conditions of Indigenous peoples are improving and whether the gaps between Indigenous peoples and other citizens have indeed narrowed. There is unsettling evidence that they may not have. It was the purpose of this study to determine how these gaps have narrowed or widened during the decade 1990 to 2000. Census data and life expectancy estimates from government sources were used to adapt the Human Development Index (HDI) to examine how the broad social, economic, and health status of Indigenous populations in these countries have changed since 1990. Three indices - life expectancy, educational attainment, and income - were combined into a single HDI measure. Between 1990 and 2000, the HDI scores of Indigenous peoples in North America and New Zealand improved at a faster rate than the general populations, closing the gap in human development. In Australia, the HDI scores of Indigenous peoples decreased while the general populations improved, widening the gap in human development. While these countries are considered to have high human development according to the UNDP, the Indigenous populations that reside within them have only medium levels of human development. The inconsistent progress in the health and well-being of Indigenous populations over time, and relative to non-Indigenous populations, points to the need for further efforts to improve the social, economic, and physical health of Indigenous peoples.


Stimulable phosphor plates in chest radiology.
The stimulable phosphor plate technique has revolutionised radiology with portable equipment. The image quality permits diagnosis under difficult control conditions (ICUs). In order to achieve a signal-to-noise ratio, and therefore a contrast resolution similar to the commonly used film/screen systems, a higher radiation dose is needed. However, overall, with this technique a radiation dose reduction may be achieved as a result of the elimination of the need for retakes. The available stimulable phosphor plate systems, with adequate image processing are reliable, and at least as good as conventional film/screen systems for diagnosis in chest radiography. There are, however, other aspects that make the stimulable phosphor plate technique particularly appealing. Firstly, its reproducibility, which particularly in chest radiography allows images to be obtained with the same grey scale and darkness. Secondly, as this technique permits digital archiving and visualisation of images on screen, images can be rapidly distributed over a network making them available when and where they are needed.


Pest categorisation of Colletotrichum fructicola.
The EFSA Plant Health Panel performed a pest categorisation of Colletotrichum fructicola Prihast., a well-defined polyphagous fungus of the C. gloeosporioides complex which has been reported from all the five continents to cause anthracnose, bitter rot and leaf spotting diseases on over 90 cultivated and non-cultivated woody or herbaceous plant species. The pathogen is not included in EU Commission Implementing Regulation 2019/2072. Because of the very wide host range, this pest categorisation focused on Camellia sinensis, Citrus sinensis, C. reticulata, Fragaria × ananassa, Malus domestica, M. pumila, Persea americana, Prunus persica, Pyrus pyrifolia and P. bretschneideri for which there was robust evidence that C. fructicola was formally identified by morphology and multilocus gene sequencing analysis. Host plants for planting and fresh fruits are the main pathways for the entry of the pathogen into the EU. There are no reports of interceptions of C. fructicola in the EU. The pathogen has been reported from Italy and France. The host availability and climate suitability factors occurring in some parts of the EU are favourable for the establishment of the pathogen. Economic impact on the production of the main hosts is expected if establishment occurs. Phytosanitary measures are available to prevent the re-introduction of the pathogen into the EU. Although the pathogen is present in the EU, there is a high uncertainty on its actual distribution in the territory because of the re-evaluation of Colletotrichum taxonomy and the lack of systematic surveys. Therefore, the Panel cannot conclude with certainty on whether C. fructicola satisfies the criterium of being present but not widely distributed in the EU to be regarded as a potential Union quarantine pest unless systematic surveys for C. fructicola are conducted and Colletotrichum isolates from the EU in culture collections are re-evaluated.


Antibodies to gliadin detected by immunofluorescence and a micro-ELISA method: markers of active childhood and adult coeliac disease.
Antibodies to gliadin have been detected by immunofluorescence (IFL-AGA) and a micro-ELISA method (ELISA-AGA) in 45 out of 47 (96%) sera from patients with active childhood and adult coeliac disease. The two methods were more sensitive than R1-reticulin antibodies (R1-ARA) which were found only in 28 of the same patients (60%). R1-ARA were always negative in the 26 sera from patients with childhood coeliac disease and adult coeliac disease after gluten free diet, while IFL- and ELISA-AGA were respectively found in three (12%) and in four (15%) out of these patients. Moreover, while R1-ARA and IFL-AGA were strictly confined to coeliac disease. ELISA-AGA were occasionally found in patients with control diseases. These 'false positive' antibodies were all of IgG class and had low titres. In our experience IFL- and ELISA-AGA of IgA class were strictly confined to active childhood coeliac disease and adult coeliac disease. The detection of AGA is useful in monitoring the diet and in the follow up of coeliac disease. IFL- and ELISA-AGA, then, are to be preferred to R1-ARA for the screening of coeliac patients.


Controversies in laparoscopic ventral hernia repair.
The introduction of laparoscopy as a surgical technique provided a method preventing major abdominal wall incisions and improving recovery of the patient after surgery. In abdominal wall surgery laparoscopic ventral hernia repair has proven to be at least as save as open repair. However, the technique of laparoscopic ventral hernia repair has not been standardized. Despite all the research that has been conducted and all the articles that were published, there still seems to be absence of consensus about the best method to repair a ventral hernia. To review knowledge on incisional hernias and discuss several controversies regarding the laparoscopic management of ventral hernias. A review of the literature was undertaken. A search identified twenty records: six RCTs on incisional hernias, five RCTs on ventral hernias and nine reviews or meta-analyses. Interpretation of the scientific data is difficult because the outcomes in literature are often based on pooled data of primary ventral hernias and incisional ventral hernias. Controversy remains regarding the optimal laparoscopic management of ventral hernias in terms of selection of patients for laparoscopic repair, optimal technique, outcomes and cost-efficacy. Lack of evidence allows persisting controversies in laparoscopic ventral hernia repair. RCTs and registries are necessary to document efficacy, morbidity, quality of life and costs during a sufficient period of time to provide clinicians with the evidence required to make the right choice for the best surgical technique.


Go with the FLOW: Implementation of a psychological skills intervention in an exercise program for post-bariatric surgery patients.
Bariatric surgery is an effective obesity treatment; however, most individuals regain weight following surgery. Following a Lifestyle of Wellness (FLOW) is a psychological skills intervention with strategies designed to increase self-efficacy and promote living a healthy lifestyle including regular physical activity. Eleven participants completed FLOW. Results indicated participants enjoyed the program and intended to continue this lifestyle upon program completion. Interviews indicated FLOW was effective for improving self-perceptions, and exercise motivation. The most effective sessions were goal setting, future planning, and stress management. Suggestions for program improvement were provided. This information can be used to improve the FLOW program and for implementation into other settings.


Reverse Right Ventricular Remodeling After Lung Transplantation in Patients With Pulmonary Arterial Hypertension Under Combination Therapy of Targeted Medical Drugs.
Patients with pulmonary arterial hypertension (PAH) are currently treated with combination therapy of PAH-targeted drugs. Reverse right ventricular (RV) remodeling after lung transplantation (LTx) in patients with end-stage PAH despite combination therapy of PAH-targeted drugs has not been fully elucidated.Methods and Results:A total of 136 patients, including 32 with PAH, underwent LTx from 1998 to 2014. We enrolled 12 consecutive patients with PAH treated with combination therapy of PAH-targeted drugs who underwent LTx and retrospectively analyzed the temporal and serial changes in hemodynamics and echocardiography before LTx and at 3 and 12 months after LTx. Before LTx, the RV was markedly dilated with substantially reduced RV fractional area change (RVFAC). At 3 months after LTx, pulmonary artery pressure, pulmonary vascular resistance and RV stroke work index were significantly decreased, while left ventricular stroke work index was increased. RV size assessed by echocardiography also significantly decreased and RVFAC improved. At 12 months after LTx, RVFAC was further increased and RV wall thickness was decreased significantly. Although severe RV dysfunction and dilation were observed in patients with end-stage PAH despite combination therapy of PAH-targeted drugs, RV function and morphology were improved after reduction of RV pressure load by LTx.


Health plan administrative records versus birth certificate records: quality of race and ethnicity information in children.
To understand racial and ethnic disparities in health care utilization and their potential underlying causes, valid information on race and ethnicity is necessary. However, the validity of pediatric race and ethnicity information in administrative records from large integrated health care systems using electronic medical records is largely unknown. Information on race and ethnicity of 325,810 children born between 1998-2008 was extracted from health plan administrative records and compared to birth certificate records. Positive predictive values (PPV) were calculated for correct classification of race and ethnicity in administrative records compared to birth certificate records. Misclassification of ethnicity and race in administrative records occurred in 23.1% and 33.6% children, respectively; the majority due to missing ethnicity (48.3%) and race (40.9%) information. Misclassification was most common in children of minority groups. PPV for White, Black, Asian/Pacific Islander, American Indian/Alaskan Native, multiple and other was 89.3%, 86.6%, 73.8%, 18.2%, 51.8% and 1.2%, respectively. PPV for Hispanic ethnicity was 95.6%. Racial and ethnic information improved with increasing number of medical visits. Subgroup analyses comparing racial classification between non-Hispanics and Hispanics showed White, Black and Asian race was more accurate among non-Hispanics than Hispanics. In children, race and ethnicity information from administrative records has significant limitations in accurately identifying small minority groups. These results suggest that the quality of racial information obtained from administrative records may benefit from additional supplementation by birth certificate data.


Learning robust perceptive locomotion for quadrupedal robots in the wild.
Legged robots that can operate autonomously in remote and hazardous environments will greatly increase opportunities for exploration into underexplored areas. Exteroceptive perception is crucial for fast and energy-efficient locomotion: Perceiving the terrain before making contact with it enables planning and adaptation of the gait ahead of time to maintain speed and stability. However, using exteroceptive perception robustly for locomotion has remained a grand challenge in robotics. Snow, vegetation, and water visually appear as obstacles on which the robot cannot step or are missing altogether due to high reflectance. In addition, depth perception can degrade due to difficult lighting, dust, fog, reflective or transparent surfaces, sensor occlusion, and more. For this reason, the most robust and general solutions to legged locomotion to date rely solely on proprioception. This severely limits locomotion speed because the robot has to physically feel out the terrain before adapting its gait accordingly. Here, we present a robust and general solution to integrating exteroceptive and proprioceptive perception for legged locomotion. We leverage an attention-based recurrent encoder that integrates proprioceptive and exteroceptive input. The encoder is trained end to end and learns to seamlessly combine the different perception modalities without resorting to heuristics. The result is a legged locomotion controller with high robustness and speed. The controller was tested in a variety of challenging natural and urban environments over multiple seasons and completed an hour-long hike in the Alps in the time recommended for human hikers.


Greater Progression of Age-Related Aortic Stiffening in Adults with Poor Trunk Flexibility: A 5-Year Longitudinal Study.
Purpose: Having a low level of physical fitness, especially cardiorespiratory fitness, appears to accelerate age-related aortic stiffening. Whereas, some studies have reported that trunk flexibility is a component of physical fitness, it is also negatively associated with arterial stiffening independent of cardiorespiratory fitness in cross-sectional studies. However, no long-term longitudinal study has determined whether poor trunk flexibility accelerates the progression of age-related aortic stiffening. We examined trunk flexibility and aortic stiffness progression in a 5-year longitudinal study. Methods and Results: A total of 305 apparently healthy men and women participated in this study (49.6 ± 9.5 years of age). Trunk flexibility was measured using a sit-and-reach test. Aortic stiffness was assessed using carotid-femoral pulse wave velocity (cfPWV) at baseline and after 5 years. Analysis of covariance (ANCOVA) was used to assess the association of the annual rate of cfPWV across flexibility levels (low, middle, high). There were no significant differences in baseline cfPWV among the three groups (835 ± 164, 853 ± 140, 855 ± 2.68 cm/s; P = 0.577). Annual ΔcfPWV was significantly higher in the low-flexibility group than in the high-flexibility group (P = 0.009). ANCOVA revealed an inverse relationship between flexibility level and annual ΔcfPWV (14.41 ± 2.73, 9.79 ± 2.59, 2.62 ± 2.68 cm/s/year; P for trend = 0.011). Multiple regression analysis revealed that baseline sit and reach (β = -0.12, -0.70 to -0.01) was independently correlated with ΔcfPWV following adjustment for baseline peak oxygen uptake, age, sex, body fat, heart rate, and cfPWV. The 5-year change in cfPWV was not significantly correlated with 5-year change in sit-and-reach performance (P = 0.859). Conclusion: Poor trunk flexibility is associated with greater progression of age-related aortic stiffening in healthy adults. However, we failed to confirm a significant association between 5-year change in aortic stiffness and 5-year change in trunk flexibility. The association between increased age-related increase in aortic stiffness and deterioration in flexibility due to age may require observation for more than 5 years.


Proteomics analysis of human coronary atherosclerotic plaque: a feasibility study of direct tissue proteomics by liquid chromatography and tandem mass spectrometry.
Cardiovascular disease presents significant variations in human populations with respect to the atherosclerotic plaque progression, inflammation, thrombosis, and rupture. To gain a more comprehensive picture of the pathogenic mechanism of atherosclerosis and the variations seen in patients, efficient methods to identify proteins from the normal and diseased arteries need to be developed. To accomplish this goal, we tested the feasibility and efficiency of protein identification by a recently developed method, termed direct tissue proteomics (DTP). We analyzed frozen and paraformaldehyde-fixed archival coronary arteries with the DTP method. We also validated the distinct expression of four proteins by immunohistochemistry. In addition, we demonstrated the compatibility of the DTP method with laser capture microdissection and the possibility of monitoring specific cytokines and growth factors by the absolute quantification of abundance method. Major findings from this feasibility study are that 1) DTP can be used to efficiently identify proteins from paraformaldehyde-fixed, paraffin-embedded, and frozen coronary arteries; 2) approximately twice the number of proteins were identified from the frozen sections when compared with the paraformaldehyde-fixed sections; 3) laser capture microdissection is compatible with DTP; and 4) detection of low abundance cytokines and growth factors in the coronary arteries required selective reaction monitoring experiments coupled to absolute quantification of abundance. The analysis of 35 human coronary atherosclerotic samples allowed identification of a total of 806 proteins. The present study provides the first large scale proteomics map of human coronary atherosclerotic plaques.


Association of PAEs with Precocious Puberty in Children: A Systematic Review and Meta-Analysis.
Precocious puberty (PP) currently affects 1 in 5000 children and is 10 times more common in girls. Existing studies have tried to detect an association between phathalic acid esters (PAEs) and PP, but the results did not reach a consensus. To estimate the association between PAEs and children with PP based on current evidence. Databases including PubMed (1978 to March 2015), OVID (1946 to March 2015), Web of Science (1970 to March 2015), EBSCO (1976 to March 2015), CNKI (1979 to March 2015), WANFANG DATA (1987 to March 2015), CBM (1978 to March 2015) and CQVIP (1989 to March 2015) were searched to identify all case-control studies that determined the exposure and concentration of PAEs and their metabolites in children with PP. Meta-analysis of the pooled standard mean difference (SMD) and odds ratio (OR) with 95% confidence intervals (CI) were calculated. A total of 14 studies involving 2223 subjects were finally included. The pooled estimates showed that PP was associated with di-(2-ethylhexyl)-phthalate (DEHP) exposure (OR: 3.90, 95% CI: 2.77 to 5.49). Besides, the concentration of DEHP (SMD: 1.73, 95% CI: 0.54 to 2.91) and di-n-butyl phthalate (DBP) (SMD: 4.31, 95% CI: 2.67 to 5.95) in the PP group were significantly higher than those in the control group, respectively, while no difference was detected between case and control groups in either serum or urinary concentration of mono-(2-ethylhexyl)-phthalate (MEHP), monobutyl phthalate (MBP), mono(2-ethyl-5-oxohexyl) phthalate(MEOHP), mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), monomethyl phthalate (MMP), monobenzyl phthalate (MBzP) or monoethyl phthalate (MEP). Exposure of DEHP and DBP might be associated with PP risk for girls, however, there is no evidence to show an association between the exposure to most PAE metabolites and PP. Given the moderate strength of the results, well-designed cohort studies with large sample size should be performed in future.


If it's difficult to pronounce, it must be risky.
Low processing fluency fosters the impression that a stimulus is unfamiliar, which in turn results in perceptions of higher risk, independent of whether the risk is desirable or undesirable. In Studies 1 and 2, ostensible food additives were rated as more harmful when their names were difficult to pronounce than when their names were easy to pronounce; mediation analyses indicated that this effect was mediated by the perceived novelty of the substance. In Study 3, amusement-park rides were rated as more likely to make one sick (an undesirable risk) and also as more exciting and adventurous (a desirable risk) when their names were difficult to pronounce than when their names were easy to pronounce.


Cross-species transmission and recombination of 'AIDS' viruses.
Acquired Immune Deficiency Syndrome (AIDS) is caused by two different Human Immunodeficiency Viruses, HIV-1 and HIV-2. Closely related viruses (SIVs) are found in many species of non-human primates. Phylogenetic analyses indicate that cross-species transmission events have been quite frequent. Both HIV-1 and HIV-2 appear to have resulted from multiple transfers of lentiviruses naturally infecting other primates; the source of HIV-2 appears to have been sooty mangabeys, whereas for HIV-1 the source may have been chimpanzees. Phylogenetic analyses also provide evidence that recombination has occurred between divergent viruses in vivo. Evolutionary trees based on various regions of the viral genome generally have consistent branching orders. However, some isolates fall into significantly different phylogenetic positions, indicating that their genomes are mosaics of sequences with different evolutionary histories. This implies that co-infection with highly divergent viral strains can occur in HIV-infected humans and SIV-infected primates; this could lead to the generation of hybrid genomes with significantly altered biological properties, and also has important implications for HIV vaccine development programmes.


The emergence of neurotransmitters as immune modulators.
Initially, the idea that neurotransmitters could serve as immunomodulators emerged with the discovery that their release and diffusion from nervous tissue could lead to signaling through lymphocyte cell-surface receptors and the modulation of immune function. It is now evident that neurotransmitters can also be released from leukocytes and act as autocrine or paracrine modulators. Here, we review the data indicating that leukocytes synthesize and release 'neurotransmitters' and we also discuss the diverse effects that these compounds exert in a variety of immune cells. The role of neurotransmitters in immune-related diseases is also reviewed succinctly. Current and future developments in understanding the cross-talk between the immune and nervous systems will probably identify new avenues for treating immune-mediated diseases using agonists or antagonists of neurotransmitter receptors.


Development of a new type of anaerobic digestion process equipped with the function of nitrogen removal.
In order to develop a new type of anaerobic digestion process equipped with a nitrogen removal function, denitrification of nitrate nitrogen (NO3-N) in anaerobic acidogenesis of organic fraction of municipal waste (OFMSW) was investigated by two semi-continuous reactors. Reactor 1 and Reactor 2 were fed by 3% and 7% of solids concentration of synthetic garbage, respectively. Generation of nitrogen gas (N2) and ammonium nitrogen (NH4-N) was simultaneously observed in the low load of nitrate (NO3-N) (below 0.68 g NO3-N/L). In Reactor 1, ammonium nitrogen generation decreased as the addition of nitrate increased. Finally, the increase of the addition of nitrate resulted in the increase of acetic acid production.


Neuroimaging Markers of Mal de Débarquement Syndrome.
Mal de débarquement syndrome (MdDS) is a motion-induced disorder of oscillating vertigo that persists after the motion has ceased. The neuroimaging characteristics of the MdDS brain state have been investigated with studies on brain metabolism, structure, functional connectivity, and measurements of synchronicity. Baseline metabolism and resting-state functional connectivity studies indicate that a limbic focus in the left entorhinal cortex and amygdala may be important in the pathology of MdDS, as these structures are hypermetabolic in MdDS and exhibit increased functional connectivity to posterior sensory processing areas and reduced connectivity to the frontal and temporal cortices. Both structures are tunable with periodic stimulation, with neurons in the entorhinal cortex required for spatial navigation, acting as a critical efferent pathway to the hippocampus, and sending and receiving projections from much of the neocortex. Voxel-based morphometry measurements have revealed volume differences between MdDS and healthy controls in hubs of multiple resting-state networks including the default mode, salience, and executive control networks. In particular, volume in the bilateral anterior cingulate cortices decreases and volume in the bilateral inferior frontal gyri/anterior insulas increases with longer duration of illness. Paired with noninvasive neuromodulation interventions, functional neuroimaging with functional magnetic resonance imaging (fMRI), electroencephalography (EEG), and simultaneous fMRI-EEG have shown changes in resting-state functional connectivity that correlate with symptom modulation, particularly in the posterior default mode network. Reduced parieto-occipital connectivity with the entorhinal cortex and reduced long-range fronto-parieto-occipital connectivity correlate with symptom improvement. Though there is a general theme of desynchronization correlating with reduced MdDS symptoms, the prediction of optimal stimulation parameters for noninvasive brain stimulation in individuals with MdDS remains a challenge due to the large parameter space. However, the pairing of functional neuroimaging and noninvasive brain stimulation can serve as a probe into the biological underpinnings of MdDS and iteratively lead to optimal parameter space identification.


The relationships among sport self-perceptions and social well-being in athletes with physical disabilities.
Peer relationships account for a significant motivational influence on sport participation among youth athletes with and without disabilities. The primary purpose of this study was to determine if the quality of friendships, physical self-perceptions and general self-worth predicted close friendship, loneliness and social acceptance among 46 athletes with physical disabilities (males = 35, female = 11) between the ages of 12 and 21 (M age = 15.37, SD = 2.45). Second, this study examined descriptive information on the quality of friendships inside and outside of an adapted sport setting, feelings of loneliness, social acceptance, close friendships, athletic competence, physical appearance, and self-worth among youth athletes with physical disabilities. Participants completed the Sport Friendship Quality Scale (SFQS), a Loneliness Rating Scale and the Self-Perception Profile for Adolescents (SPPA). Three regression analyses used positive and negative aspects of non-sport friendship quality, positive aspects of sport friendship quality, physical appearance, athletic competence, and self-worth as predictors and accounted for 57%, 41%, and 31% of the variance in loneliness, close friendships, and social acceptance, respectively. Athletic competence and self-worth were the most important predictors of loneliness and close friendships with significant (p < .10) beta weights. No single predictor had a significant beta weight in predicting social acceptance. Negative and positive elements of friendship quality were not important predictors. These findings highlight the importance of global psychological (i.e., self-worth) and sport specific psychological (i.e., athletic competence) constructs in predicting important social well-being indices (i.e., close friendships & loneliness).


Evaluation of the DNA fingerprinting method AFLP as an new tool in bacterial taxonomy.
We investigated the usefulness of a novel DNA fingerprinting technique, AFLP, which is based on the selective amplification of genomic restriction fragments by PCR, to differentiate bacterial strains at the subgeneric level. In totals, 147 bacterial strains were subjected to AFLP fingerprinting: 36 Xanthomonas strains, including 23 pathovars of Xanthomonas axonopodis and six pathovars of Xanthomonas vasicola, one strain of Stenotrophomonas, 90 genotypically characterized strains comprising all 14 hybridization groups currently described in the genus Aeromonas, and four strains of each of the genera Clostridium, Bacillus, Acinetobacter, Pseudomonas and Vibrio. Depending on the genus, total genomic DNA of each bacterium was digested with a particular combination of two restriction endonucleases and the resulting fragments were ligated to restriction halfsite-specific adaptors. These adaptors served as primer-binding sites allowing the fragments to be amplified by selective PCR primers that extend beyond the adaptor and restriction site sequences. Following electrophoretic separation on 5% (w/v) polyacrylamide/8.3 M urea, amplified products could be visualized by autoradiography because one of the selective primers was radioactively labelled. The resulting banding patterns, containing approximately 30-50 visualized PCR products in the size range 80-550 bp, were captured by a high-resolution densitoscanner and further processed for computer-assisted analysis to determine band-based similarity coefficients. This study reveals extensive evidence for the applicability of AFLP in bacterial taxonomy through comparison of the newly obtained data with results previously obtained by well-established genotypic and chemotaxonomic methods such as DNA-DNA hybridization and cellular fatty acid analysis. In addition, this study clearly demonstrates the superior discriminative power of AFLP towards the differentiation of highly related bacterial strains that belong to the same species or even biovar (i.e. to characterize strains at the infrasubspecific level), highlighting the potential of this novel fingerprinting method in epidemiological and evolutionary studies.


Impacts of Zn and Cu enrichment under ocean acidification scenario on a phytoplankton community from tropical upwelling system.
Increasing dissolution of CO2 in the surface ocean is rapidly decreasing its pH and changing carbon chemistry which is further affecting marine biota in several ways. Phytoplankton response studies under the combination of elevated CO2 and trace metals are rare. We have conducted two consecutive onboard incubation experiments (R. V. Sindhu Sadhana; August 2017) in the eastern Arabian Sea (SW coast of India) during an upwelling event. A nutrient enriched diatom bloom was initiated onboard and grown under ambient (≈400 μatm, A-CO2) and high CO2 levels (≈1000 μatm; H-CO2) with different zinc (Zn; 1 nM) and copper (Cu) concentrations (1 nM, 2 nM and 8 nM). Phytoplankton community composition and the dominant genera were different during these two experiments. CO2 enrichment alone did not show any significant growth stimulating impact on the experimental community except enhanced cell density in the first experiment. Addition of Zn at A-CO2 level revealed no noticeable responses; whereas, the same treatment under H-CO2 level significantly reduced cell number. Considerably high protein content under H-CO2+Zn treatment was possibly counteracting Zn toxicity which also caused slower growth rate. Cu addition did not show any noticeable impact on growth and biomass production except increased protein content as well as decreased carbohydrate: protein ratio. This can be attributed to relatively higher protein synthesis than carbohydrate to alleviate oxidative stress generated by Cu. The centric diatom Chaetoceros and toxin producing pennate diatom Pseudo-nitzschia showed no significant response to either CO2 or Zn enrichment. Large centric diatom Leptocylindrus and Skeletonema responded positively to Zn addition in both CO2 levels. The former species showed the most sensitive response at the highest Cu and H-CO2 treatment; whereas, the pennate diatoms Nitzschia and Pseudo-nitzschia (toxigenic diatom) showed higher resilience under elevated CO2 and Cu levels. This observation indicated that in future ocean, increasing CO2 concentrations and trace metal pollution may potentially alter phytoplankton community structure and may facilitate toxigenic diatom bloom in the coastal waters.


Healthcare-associated prosthetic heart valve, aortic vascular graft, and disseminated Mycobacterium chimaera infections subsequent to open heart surgery.
We identified 10 patients with disseminated Mycobacterium chimaera infections subsequent to open-heart surgery at three European Hospitals. Infections originated from the heater-cooler unit of the heart-lung machine. Here we describe clinical aspects and treatment course of this novel clinical entity. Interdisciplinary care and follow-up of all patients was documented by the study team. Patients' characteristics, clinical manifestations, microbiological findings, and therapeutic measures including surgical reinterventions were reviewed and treatment outcomes are described. The 10 patients comprise a 1-year-old child and nine adults with a median age of 61 years (range 36-76 years). The median duration from cardiac surgery to diagnosis was 21 (range 5-40) months. All patients had prosthetic material-associated infections with either prosthetic valve endocarditis, aortic graft infection, myocarditis, or infection of the prosthetic material following banding of the pulmonary artery. Extracardiac manifestations preceded cardiovascular disease in some cases. Despite targeted antimicrobial therapy, M. chimaera infection required cardiosurgical reinterventions in eight patients. Six out of 10 patients experienced breakthrough infections, of which four were fatal. Three patients are in a post-treatment monitoring period. Healthcare-associated infections due to M. chimaera occurred in patients subsequent to cardiac surgery with extracorporeal circulation and implantation of prosthetic material. Infections became clinically apparent after a time lag of months to years. Mycobacterium chimaera infections are easily missed by routine bacterial diagnostics and outcome is poor despite long-term antimycobacterial therapy, probably because biofilm formation hinders eradication of pathogens.


Long-term exposure of Sitka spruce seedlings to trichloroacetic acid.
Trichloroacetic acid (TCA) has been implicated as an airborne pollutant responsible for adverse effects on forest health. There is considerable debate as to whether TCA observed in trees and forest soils is derived from atmospheric deposition or from in situ production. This experiment reports the results from treating 4-year-old Sitka spruce (Picea sitchensis (Bong.) Carr) plants in a greenhouse over a growing season with TCA supplied either to the soil or to the foliage at concentrations of 10 and 100 ng mL(-1). Similar uptake of TCA by needles was observed for both modes of treatment, with significant accumulation of TCA (300 ng g(-1) dry wt) at the higher concentration. Larger concentrations in stem tissue were seen for the foliar-applied TCA (280 ng g(-1)) than for the soil-applied TCA (70 ng g(-1)), suggesting that direct stem uptake may be important. Six months after treatments stopped, TCA concentrations in the needles of plants exposed to 100 ng mL(-1) TCA were still enhanced, showing that biological degradation of TCA in needles was slow over the winter. By contrast, no significant enhancement of TCA in soil could be detected in the directly treated soils even during the experiment. The protein content of needles treated with the higher concentration of TCA by either route was significantly smaller than for the controls, but there was no effect of TCA on the conjugation of 1-chloro-2,4-dinitrobenzene in roots nor on the conjugation of 1,2-dichloro-4-nitrobenzene in needles.


Evaluating the effect of disturbed ensemble distributions on SCFG based statistical sampling of RNA secondary structures.
Over the past years, statistical and Bayesian approaches have become increasingly appreciated to address the long-standing problem of computational RNA structure prediction. Recently, a novel probabilistic method for the prediction of RNA secondary structures from a single sequence has been studied which is based on generating statistically representative and reproducible samples of the entire ensemble of feasible structures for a particular input sequence. This method samples the possible foldings from a distribution implied by a sophisticated (traditional or length-dependent) stochastic context-free grammar (SCFG) that mirrors the standard thermodynamic model applied in modern physics-based prediction algorithms. Specifically, that grammar represents an exact probabilistic counterpart to the energy model underlying the Sfold software, which employs a sampling extension of the partition function (PF) approach to produce statistically representative subsets of the Boltzmann-weighted ensemble. Although both sampling approaches have the same worst-case time and space complexities, it has been indicated that they differ in performance (both with respect to prediction accuracy and quality of generated samples), where neither of these two competing approaches generally outperforms the other. In this work, we will consider the SCFG based approach in order to perform an analysis on how the quality of generated sample sets and the corresponding prediction accuracy changes when different degrees of disturbances are incorporated into the needed sampling probabilities. This is motivated by the fact that if the results prove to be resistant to large errors on the distinct sampling probabilities (compared to the exact ones), then it will be an indication that these probabilities do not need to be computed exactly, but it may be sufficient and more efficient to approximate them. Thus, it might then be possible to decrease the worst-case time requirements of such an SCFG based sampling method without significant accuracy losses. If, on the other hand, the quality of sampled structures can be observed to strongly react to slight disturbances, there is little hope for improving the complexity by heuristic procedures. We hence provide a reliable test for the hypothesis that a heuristic method could be implemented to improve the time scaling of RNA secondary structure prediction in the worst-case - without sacrificing much of the accuracy of the results. Our experiments indicate that absolute errors generally lead to the generation of useless sample sets, whereas relative errors seem to have only small negative impact on both the predictive accuracy and the overall quality of resulting structure samples. Based on these observations, we present some useful ideas for developing a time-reduced sampling method guaranteeing an acceptable predictive accuracy. We also discuss some inherent drawbacks that arise in the context of approximation. The key results of this paper are crucial for the design of an efficient and competitive heuristic prediction method based on the increasingly accepted and attractive statistical sampling approach. This has indeed been indicated by the construction of prototype algorithms.


Pigou in the 21st Century: a tribute on the occasion of the 100th anniversary of the publication of The Economics of Welfare.
The year 2020 marks the centennial of the publication of Arthur Cecil Pigou's magnum opus The Economics of Welfare. Pigou's pricing principles have had an enduring influence on the academic debate, with a widespread consensus having emerged among economists that Pigouvian taxes or subsidies are theoretically desirable, but politically infeasible. In this article, we revisit Pigou's contribution and argue that this consensus is somewhat spurious, particularly in two ways: (1) Economists are too quick to ignore the theoretical problems and subtleties that Pigouvian pricing still faces; (2) The wholesale skepticism concerning the political viability of Pigouvian pricing is at odds with its recent practical achievements. These two points are made by, first, outlining the theoretical and political challenges that include uncertainty about the social cost of carbon, the unclear relationship between the cost-benefit and cost-effectiveness approaches, distributional concerns, fragmented ministerial responsibilities, an unstable tax base, commitment problems, lack of acceptance and trust between government and citizens as well as incomplete international cooperation. Secondly, we discuss the recent political success of Pigouvian pricing, as evidenced by the German government's 2019 climate policy reform and the EU's Green Deal. We conclude by presenting a research agenda for addressing the remaining barriers that need to be overcome to make Pigouvian pricing a common political practice.


Pharmacokinetics of sex steroids in patients with beta thalassaemia major.
To assess the pharmacokinetics of oral, intramuscular, or transdermal hormone replacement in patients with beta thalassaemia major. Oral (testosterone undecanoate 40 mg) and intramuscular (testosterone propionate 15 mg, phenylpropionate 30 mg, isocaproate 30 mg and decanoate 50 mg) testosterone and transdermal (17 beta oestradiol 25 micrograms and 50 micrograms) oestradiol were evaluated in 21 male (16-29 years) and 11 female (19-26 years) patients with beta thalassaemia major and various forms of hypogonadism. In male patients given oral testosterone, peak testosterone concentrations were observed either two to four hours or seven hours after administration; intramuscular testosterone produced peak values seven days after injection. Transdermal 17 beta oestradiol given to female patients produced a biphasic pattern with an initial peak concentration occurring at 36 hours and a secondary rise at 84 hours. The results indicate that oral androgens should be given twice daily in cases of hypogonadism, and where growth is incomplete, lower than recommended doses. If intramuscular testosterone is used, smaller doses of 10-25 mg should be given every one to two weeks. Transdermal administration of 25-50 micrograms 17 beta oestradiol generally produces a plasma E2 value in the early to mid-follicular phase range (100-300 pmol/l). This is appropriate in adults but excessive for prepubertal girls. Diffuse iron infiltration of tissues does not seem to interfere with the absorption of androgens and oestrogens from the gut, muscle, or skin.


Study on the safety and efficacy of tocilizumab, an anti-IL-6 receptor antibody, in patients with rheumatoid arthritis complicated with AA amyloidosis.
Although treatment of rheumatoid arthritis (RA) has progressed by the use of biologics, amyloid A (AA) amyloidosis is still an intractable complication in patients with RA. In the present study, safety and efficacy of 1-year treatment with an anti-IL-6 receptor antibody tocilizumab (TCZ) on RA and AA amyloidosis were estimated. TCZ (8 mg/kg every 4 weeks) was administered to five RA patients complicated with AA amyloidosis. The primary end point was improvement in renal dysfunction and the secondary end point was CDAI at 1 year after the treatment. An improvement in the renal dysfunction, including urinary protein secretion, was found, in four patients including two patients who were refractory to etanercept, with a remarkable decrease of SAA concentration, and the progression of organ dysfunction was prevented at 1 year in all patients treated with TCZ. The mean clinical disease activity index decreased from 33.9 to 4.7 (p = 0.012) in five patients treated with TCZ for 1 year. Three non-serious adverse events were observed in two patients. TCZ ameliorates renal dysfunction in RA patients complicated with AA amyloidosis who are refractory to conventional therapies, thereby suggesting that TCZ has a potential to regulate AA amyloidosis.


Evidence for prolonged clinical benefit from initial combination antiretroviral therapy: Delta extended follow-up.
The findings from therapeutic trials in HIV infection with surrogate endpoints based on laboratory markers are only partially relevant for clinical decisions on treatment. Although the collection of clinical follow-up data from such a trial would be relatively straightforward, this rarely occurs. An important reason for this may be the perception that such data have little value because the number of participants remaining on their original allocated therapy has usually fallen substantially. Delta was an international, multicentre trial in which 3207 HIV infected individuals were randomly allocated to treatment with zidovudine (ZDV) alone, ZDV combined with didanosine (ddI) or ZDV combined with zalcitabine (ddC). Although the trial closed in September 1995, information on vital status, AIDS events, treatment changes and CD4 counts was still collected every 12 months until at least March 1997. This has allowed analyses of the longer term clinical effect of treatment. The median follow-up to date of death or last known vital status was 43 months (10th percentile 18 months; 90th percentile 55 months). The proportion of participants remaining on their allocated treatment fell steadily over time; by 4 years after trial entry, 3% remained on ZDV, 20% on ZDV + ddI and 21% on ZDV + ddC. Changes mainly involved the stopping, addition or switching of a nucleoside reverse transcriptase inhibitor (NRTIs). There was little use of protease inhibitors (PIs) or non-nucleoside reverse transcriptase inhibitors (NNRTIs) before the third year of the trial. Between the third and fourth years, regimens included a drug from one of these classes for approximately 17% of person-time in all treatment groups. Relative to ZDV monotherapy, the beneficial effects of combination therapy on mortality and disease progression rates increased significantly with time since randomization. The maximum effects on mortality were observed between 2 and 3 years, with a 48% reduction for ZDV + ddI and a 26% reduction for ZDV + ddC. These rates were observed when the original allocated treatment was received 42% and 47% of the time in the ZDV + ddI and ZDV + ddC groups, respectively. The mean CD4 count remained significantly higher (approximately 50 cells/microL) in the combination therapy groups 4 years after randomization, suggesting a projection of a clinical benefit beyond this time point. The sustained clinical effect of the initial allocation to combination therapy, particularly ZDV + ddI, was remarkable in light of the convergence of drug regimens actually received across the three treatment groups. Interpretation of this finding is not straightforward. One of the possible explanations is that the effectiveness of ddI and ddC is diminished if first used later in infection or with greater prior exposure to ZDV, although the data do not clearly support either hypothesis. This analysis highlights the value of long-term clinical follow-up of therapeutic trials in HIV infection, which should be considered in the planning of all new studies.


Purification and characterization of Nipah virus nucleocapsid protein produced in insect cells.
The nucleocapsid (N) protein of Nipah virus (NiV) is a major constituent of the viral proteins which play a role in encapsidation, regulating the transcription and replication of the viral genome. To investigate the use of a fusion system to aid the purification of the recombinant N protein for structural studies and potential use as a diagnostic reagent, the NiV N gene was cloned into the pFastBacHT vector and the His-tagged fusion protein was expressed in Sf9 insect cells by recombinant baculovirus. Western blot analysis of the recombinant fusion protein with anti-NiV antibodies produced a band of approximately 62 kDa. A time course study showed that the highest level of expression was achieved after 3 days of incubation. Electron microscopic analysis of the NiV recombinant N fusion protein purified on a nickel-nitrilotriacetic acid resin column revealed different types of structures, including spherical, ring-like, and herringbone-like particles. The light-scattering measurements of the recombinant N protein also confirmed the polydispersity of the sample with hyrdrodynamic radii of small and large types. The optical density spectra of the purified recombinant fusion protein revealed a high A(260)/A(280) ratio, indicating the presence of nucleic acids. Western blotting and enzyme-linked immunosorbent assay results showed that the recombinant N protein exhibited the antigenic sites and conformation necessary for specific antigen-antibody recognition.


What is the Incidence of Suicide in Patients with Bone and Soft Tissue Cancer? : Suicide and Sarcoma.
Patients with cancer in the United States are estimated to have a suicide incidence that is approximately twice that of the general population. Patients with bone and soft tissue cancer often have physical impairments and activity limitations develop that reduce their quality of life, which may put them at high risk for depression, anxiety, and suicidal ideation. To our knowledge, there have been no large studies determining incidence of suicide among patients with bone and soft tissue cancer; this information might allow screening of certain high-risk groups. To determine (1) the incidence of suicide in patients with bone and soft tissue cancer, (2) whether the incidence of suicide is greater in patients with bone and soft tissue cancer than it is in the general US population, and (3) any demographic and tumor characteristics associated with increased suicide incidence. A retrospective analysis of the Surveillance, Epidemiology, and End Results (SEER) program was performed. A total of 23,620 patients with primary bone and soft tissue cancer were identified in this database from 1973 and 2013. Patients with a cause of death listed as "suicide and self-inflicted injury" were considered to have committed suicide and suicide incidences were determined for different demographic and tumor characteristics in this subset of patients. Patient data for age, gender, race, marital status, year of diagnosis, primary cancer site, cancer stage, course of treatment, and survival time were collected and analyzed. The incidence of suicide in patients with bone and soft tissue sarcoma was compared with the age-, gender-, and race-adjusted incidence of suicide in the general US population from 1970 to 2013 available from the National Center for Health Statistics through the SEER Program. The overall suicide incidence in this population was 32 per 100,000 person-years, which was higher than the age-, race-, and gender-adjusted US general population suicide incidence of 13 per 100,000 person-years. When compared with the incidence of suicide in matched subgroups of the general US population, a higher suicide incidence was observed in men (standardized mortality ratio [SMR], 2.49; 95% CI, 1.92-3.22; p < 0.001), patients of white race (SMR, 2.68; 95% CI, 1.94-3.56; p < 0.001), patients 21 to 30 years old (SMR, 4.40; 95% CI, 3.44-5.54; p < 0.001) and 61 to 70 years old (SMR, 3.27; 95% CI, 2.54-4.18; p < 0.001), patients with cancer of the vertebral column (SMR, 2.88; 95% CI, 2.13-3.83; p < 0.001) and pelvic bones (SMR, 2.75; 95% CI, 2.00-3.65; p < 0.001), and patients within the first 5 years of cancer diagnosis (SMR, 10.8; 95% CI, 9.19-12.61; p < 0.001). With identification of these characteristics that are associated with higher incidence of suicide, physicians should consider screening patients possessing these traits. By identifying at-risk patients, we can hope to reduce the incidence of suicide in this population by providing the treatment that these patients need. Further research must be done to determine how best to screen these patients and to identify the best interventions to reduce suicide incidence. Level III, prognostic study.


Neurobiological correlates of social conformity and independence during mental rotation.
When individual judgment conflicts with a group, the individual will often conform his judgment to that of the group. Conformity might arise at an executive level of decision making, or it might arise because the social setting alters the individual's perception of the world. We used functional magnetic resonance imaging and a task of mental rotation in the context of peer pressure to investigate the neural basis of individualistic and conforming behavior in the face of wrong information. Conformity was associated with functional changes in an occipital-parietal network, especially when the wrong information originated from other people. Independence was associated with increased amygdala and caudate activity, findings consistent with the assumptions of social norm theory about the behavioral saliency of standing alone. These findings provide the first biological evidence for the involvement of perceptual and emotional processes during social conformity.


Purified canola lutein selectively inhibits specific isoforms of mammalian DNA polymerases and reduces inflammatory response.
In the screening of DNA polymerase (pol) inhibitor, we isolated lutein, a carotenoid, from the crude (unrefined) pressed oil of canola (low erucic acid rapeseed, Brassica napus L.). Commercially prepared carotenoids such as lutein (1), zeaxanthin (2), beta-cryptoxanthin (3), astaxanthin (4), canthaxanthin (5), beta-carotene (6), lycopene (7), capsanthin (8), fucoxanthin (9) and fucoxanthinol (10), were investigated for the inhibitory activities of pols. Compounds 1, 2 and 8 exhibited strong inhibition of the activities of mammalian pols beta and lambda, which are DNA repair- and/or recombination-related pols. On the other hand, all carotenoids tested had no influence on the activity of a mammalian pol alpha, which is a DNA replicative pol. Lutein (1) was the strongest pol inhibitor of mammalian pols beta and lambda in the prepared ten carotenoids tested, but did not influence of the activities of mammalian pols alpha, gamma, delta and epsilon. The tendency for pols beta and lambda inhibition by these carotenoids showed a positive correlation with the suppression of TPA (12-O-tetradecanoylphorbol-13-acetate)-induced inflammation. These results suggest that cold pressed unrefined canola/rapeseed oil, or other oils with high levels of lutein and other carotenoids, may be useful for their anti-inflammatory properties.


Burden of disease due to amphetamines, cannabis, cocaine, and opioid use disorders in South America, 1990-2019: a systematic analysis of the Global Burden of Disease Study 2019.
South America's substance use profile, poverty, income inequality, and cocaine-supplier role make it a unique place for substance use research. This study investigated the burden of disease attributable to amphetamine use disorder, cannabis use disorder (CAD), cocaine use disorder, and opioid use disorder (OUD) in South America from 1990 to 2019, on the basis of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019. GBD 2019 estimated the incidence, prevalence, mortality, years of life lost (YLL), years of life lived with disability (YLD), and disability-adjusted life-years (DALYs) due to substance use disorders in each of the 12 South American countries (Argentina, Bolivia, Brazil, Chile, Colombia, Ecuador, Guyana, Paraguay, Peru, Suriname, Uruguay, and Venezuela). Data were modelled using standardised tools (ie, the Cause of Death Ensemble model, spatio-temporal Gaussian process regression, and disease modelling meta-regression) to generate estimates of each quantity of interest by sex, location, and year. The analysis included comparisons by sex and country, and against regional and global estimates. In 2019, the highest amphetamine use disorder burden per 100 000 population in South America was in Peru (66 DALYs). CAD DALY rates per 100 000 in South America were stable between 1990 and 2019, except in Chile and Colombia, which had the highest rates in 2019 (19 DALYs for Chile and 18 DALYs for Colombia). OUD DALYs per 100 000 increased during the period in Brazil and Peru, which in 2019 had the highest rates in South America (82 DALYs for Brazil and 70 DALYs for Peru). In 2019, Brazil had the highest cocaine use disorder DALYs per 100 000 (45 DALYs), nearly double its rate in 1990. DALY rates were higher in males than females for each substance use disorder, except in Paraguay. The overall burden of substance use disorders was higher in males than in females, mainly because of cocaine use disorder and CAD, whereas for amphetamine use disorder, the difference between sexes was minimal, and for OUD there was no difference. For males and females, the highest rate of substance use disorders DALYs per 100 000 was for OUD except in Argentina (in males, 58 DALYs for cocaine use disorder vs 52 DALYs for OUD) and in Paraguay (in females, 77 for amphetamine use disorder vs 50 for OUD). CAD DALY rates were generally the lowest among the substance use disorders for males and females. Amphetamine use disorder YLD rates were reasonably stable throughout the period and were highest in Peru, Paraguay, and Uruguay (>40 YLD per 100 000). For CAD, YLD rates were stable in all countries except Chile and Colombia. Cocaine use disorder YLD rates per 100 000 for the top four countries (Argentina, Uruguay, Chile, and Brazil) increased from 1990 to 2010 (eg, from 19 to 33 in Brazil), but decreased between 2010 and 2019 (eg, from 36 to 31 in Chile). For OUD, YLD rates showed a slight increase in most countries apart from Brazil, which increased from 52 in 1990 to 80 in 2019 and was top among the countries. Amphetamine use disorder YLL rates per 100 000 were highest in Suriname and Peru during the period, although in Suriname it increased from 2·7 in 2010 to 3·2 in 2019, whereas in Peru it decreased from 2·1 to 1·7. The highest YLL rate for cocaine use disorder was in Brazil, which increased from 3·7 in 1990 to 18·1 in 2019. Between 2000 and 2019, Chile and Uruguay showed the highest OUD YLL rates (11·6 for Chile and 10·9 for Uruguay). A high incidence of CAD was found in Chile, Colombia, Guyana, and Suriname. There were high incidences of amphetamine use disorder in Paraguay, cocaine use disorder in Argentina, and OUD in Ecuador. A decrease in annual prevalence for substance use disorders during the period was observed in Venezuela (amphetamine use disorder, CAD, and OUD), Brazil (CAD and amphetamine use disorder), Colombia (amphetamine use disorder and cocaine use disorder), Peru (amphetamine use disorder and cocaine use disorder), Chile and Suriname (amphetamine use disorder), Uruguay (CAD), and Bolivia (OUD). Overall, the cocaine use disorder burden stabilised then decreased. OUD was less prevalent than other substance use disorders but its burden was the highest. The decrease in the burden of cocaine use disorder probably reflects the success of national standardised treatment programmes. Programmes for amphetamine use disorder, CAD, and OUD management should be improved. We did not find an increase in CAD burden in Uruguay, the country with the highest degree of cannabis decriminalisation in the region. Countries in South America should improve monitoring of substance use disorders, including regular surveys to provide more accurate data on which to base policy decisions. The Bill & Melinda Gates Foundation.


Ecosystem Composition Controls the Fate of Rare Earth Elements during Incipient Soil Genesis.
The rare earth elements (REE) are increasingly important in a variety of science and economic fields, including (bio)geosciences, paleoecology, astrobiology, and mining. However, REE distribution in early rock-microbe-plant systems has remained elusive. We tested the hypothesis that REE mass-partitioning during incipient weathering of basalt, rhyolite, granite and schist depends on the activity of microbes, vascular plants (Buffalo grass), and arbuscular mycorrhiza. Pore-water element abundances revealed a rapid transition from abiotic to biotic signatures of weathering, the latter associated with smaller aqueous loss and larger plant uptake. Abiotic dissolution was 39% of total denudation in plant-microbes-mycorrhiza treatment. Microbes incremented denudation, particularly in rhyolite, and this resulted in decreased bioavailable solid pools in this rock. Total mobilization (aqueous + uptake) was ten times greater in planted compared to abiotic treatments, REE masses in plant generally exceeding those in water. Larger plants increased bioavailable solid pools, consistent with enhanced soil genesis. Mycorrhiza generally had a positive effect on total mobilization. The main mechanism behind incipient REE weathering was carbonation enhanced by biotic respiration, the denudation patterns being largely dictated by mineralogy. A consistent biotic signature was observed in La:phosphate and mobilization: solid pool ratios, and in the pattern of denudation and uptake.


Cytodifferentiation in the rosy mutant of Drosophila melanogaster.
In the rosy mutant of Drosophila melanogaster, two types of autofluorescent cytoplasmic inclusions are found in the cells of the posterior region of the fatbody at the prepupal stage. Bright yellow autofluorescent granules accumulating within larger inclusions clearly demarcate this area of the fatbody which also contains cobalt blue fluorescent globular material. Such inclusions were not noted in the normal Ore-R strain at this stage nor in the series of mutant strains examined other than the rosy(2) and maroon-like mutants. The pattern of biochemical deviation of the latter two mutants is known to be identical to that of the rosy mutant, and a portion of this mutant upset can be ascribed to the absence of xanthine dehydrogenase. These mutants lack the products of enzyme activity, uric acid and isoxanthopterin, and accumulate their precursors, hypoxanthine and 2-amino-4-hydroxypteridine. Chromatographic studies on the fatbody of rosy prepupae have shown that 2-amino-4-hydroxypteridine is limited to the posterior region; this correspondence in location as well as color of fluorescence indicates that the cobalt blue auto fluorescent globules in the fatbody contain 2-amino-4-hydroxypteridine. In the normal strain, isoxanthopterin was identified in the chromatograms of the posterior region of the fatbody, but it was not obtained from the anterior region of the fatbody. On the other hand, xanthine dehydrogenase activity could be demonstrated throughout the fatbody of the normal strain. The restriction of isoxanthopterin to a certain group of fat cells in the wild type strain and its absence from other fat cells can be explained by the differential distribution of its immediate precursor, 2-amino-4-hydroxypteridine, as displayed in the mutant rosy.


Overlaying multiple sources of data to identify bottlenecks in clinical workflow.
The pursuit of increased efficiency and quality of clinical care based on the analysis of workflow has seen the introduction of several modern technologies into medical environments. Electronic health records (EHRs) remain central to analysis of workflow, owing to their wide-ranging impact on clinical processes. The two most common interventions to facilitate EHR-related workflow analysis are automated location tracking using sensor-based technologies and EHR usage data logs. However, to maximize the potential of these technologies, and especially to facilitate workflow redesign, it is necessary to overlay these quantitative findings on the contextual data from qualitative methods such as ethnography. Such a complementary approach promises to yield more precise measures of clinical workflow that provide insights into how redesign could address inefficiencies. In this paper, we categorize clinical workflow in the Emergency Department (ED) into three types (perceived, real and ideal) to create a structured approach to workflow redesign using the available data. We use diverse data sources: sensor-based location tracking through Radio-Frequency Identification (RFID), summary EHR usage data logs, and data from physician interviews augmented by direct observations (through clinician shadowing). Our goal is to discover inefficiencies and bottlenecks that can be addressed to achieve a more ideal workflow state relative to its real and perceived state. We thereby seek to demonstrate a novel data-driven approach toward iterative workflow redesign that generalizes for use in a variety of settings. We also propose types of targeted support or adjustments to offset some of the inefficiencies we noted.


Association of serum alkaline phosphatase with coronary artery calcification in maintenance hemodialysis patients.
Recent in vitro studies have shown a link between alkaline phosphatase and vascular calcification in patients with chronic kidney disease (CKD). High serum levels of alkaline phosphatase are associated with increased death risk in epidemiologic studies of maintenance hemodialysis (MHD) patients. We hypothesized that coronary artery calcification is independently associated with increased serum alkaline phosphatase levels in MHD patients. We examined the association of coronary artery calcification score (CACS) and alkaline phosphatase in 137 randomly selected MHD patients for whom markers of malnutrition, inflammation, and bone and mineral disorders were also measured. Serum alkaline phosphatase was the only measure with significant and robust association with CACS (P < 0.003), whereas either other biochemical markers had no association with CACS or their association was eliminated after controlling for case-mix variables. Serum alkaline phosphatase >120 IU/L was a robust predictor of higher CACS and was particularly associated with the likelihood of CACS >400 (multivariate odds ratio 5.0 95% confidence interval 1.6 to 16.3; P = 0.007). Serum alkaline phosphatase of approximately 85 IU/L seemed to be associated with the lowest likelihood of severe coronary artery calcification, but in the lowest tertile of alkaline phosphatase, the CACS predictability was not statistically significant. An association between serum alkaline phosphatase level and CACS exists in MHD patients. Given the high burden of vascular calcification in patients with CKD, examining potential therapeutic interventions to modulate the alkaline phosphatase pathway may be warranted.


HIV testing, antiretroviral therapy, and treatment outcomes in new cases of tuberculosis in Brazil, 2011.
Objective To assess the implementation of HIV-related interventions for patients with tuberculosis (TB), as well as TB treatment outcomes in patients coinfected with HIV in Brazil in 2011. Methods This was a cross-sectional, operational research study of HIV-related interventions among TB cases and the sociodemographic and clinical characteristics of TB-HIV coinfected patients. It also used a retrospective cohort design to determine the association between antiretroviral therapy (ART) and favorable TB treatment outcomes. The source of data was a linkage of 2011 administrative health databases used by the National TB and HIV/AIDS Programs. Results Of 73 741 new cases of TB reported, 63.6% (46 865 patients) were tested for HIV; 10.3% were positive. Of patients with HIV, 45.9% or 3 502 were on ART. TB favorable outcome was achieved in 63.1% or 2 205 coinfected patients on ART and in only 35.4% or 1 459 of those not on ART. On multivariate analysis, the relative risk for the association between ART and TB treatment success was 1.72 (95% Confidence Interval = 1.64-1.81). Conclusions The linkage between national TB and HIV datasets has created a convenient baseline for ongoing monitoring of HIV testing, ART use, and TB treatment outcomes among coinfected patients. The low rates of HIV screening and ART use in 2011 need to be improved. The association between ART and treatment success adds to the evidence supporting timely initiation of ART for all patients with TB-HIV coinfection.


Increased mortality in young candidemia patients associated with presence of a Candida albicans general-purpose genotype.
The yeast Candida albicans causes life-threatening candidemia. A general-purpose genotype (GPG; corresponds to clade 1) causes more infections than other C. albicans genotypes. To investigate if GPG strains also cause higher mortality, we developed a duplex PCR assay which was 98% accurate in identifying GPG strains in an international collection of strains typed with probe Ca3. We applied the assay to 635 European C. albicans candidemia isolates. Of these, 18% conformed to the GPG genotype, 4% were of a borderline genotype, and 78% were of a non-GPG genotype, broadly consistent with genotype distributions in earlier studies. The prevalence of GPG strains was increased in females and in younger patients, exceeding 40% in infants aged ≤1 year. Logistic regression confirmed sex and age as significant determinants of GPG prevalence. Across the entire patient cohort, there was no difference in mortality for patients infected with GPG strains or other strains (36% versus 37%). However, mortality in patients aged ≤48 years was 33% for infection with GPG strains but only 15% for infection with other strains (z test; P < 0.01). Mortality rates associated with GPG and non-GPG strains were comparable in older patients (39% versus 46%). A logistic regression analysis confirmed the age-dependent impact of genotype on mortality. Thus, GPG strains may be more virulent than other strains in younger patients. Because candidemia is usually caused by endogenous strains, our PCR assay could potentially be used as a risk assessment tool for identifying younger patients most at risk of death from candidemia.


Enhanced DC-Operated Electroluminescence of Forwardly Aligned p/MQW/n InGaN Nanorod LEDs via DC Offset-AC Dielectrophoresis.
We introduce an orientation-controlled alignment process of p-GaN/InGaN multiquantum-well/n-GaN (p/MQW/n InGaN) nanorod light-emitting diodes (LEDs) by applying the direct current (DC) offset-alternating current (AC) or pulsed DC electric fields across interdigitated metal electrodes. The as-forwardly aligned p/MQW/n InGaN nanorod LEDs by a pulsed DC dielectrophoresis (DEP) assembly process improve the electroluminescence (EL) intensities by 1.8 times compared to the conventional AC DEP assembly process under DC electric field operation and exhibit an enhanced applied current and EL brightness in the current-voltage and EL intensity-voltage curves, which can be directly used as the fundamental data to construct DC-operated nanorod LED devices, such as LED areal surface lightings, scalable lightings (micrometers to inches) and formable surface lightings. The enhancement in the applied current, the improved EL intensity, and the increased number of forwardly aligned p/MQW/n InGaN nanorods in panchromatic cathodoluminescence images confirm the considerable enhancement of forwardly aligned one-dimensional nanorod LEDs between two opposite electrodes using DC offset-AC or a pulsed DC electric field DEP assembly process. These DC offset-AC or pulsed DC electric field DEP assembly processes suggest that designing for these types of interactions could yield new ways to control the orientation of asymmetric p/MQW/n InGaN diode-type LED nanorods with a relatively low aspect ratio.


Expression of glutamine transporter isoforms in cerebral cortex of rats with chronic hepatic encephalopathy.
Hepatic encephalopathy (HE) is a neuropsychiatric disorder that occurs due to acute and chronic liver diseases, the hallmark of which is the increased levels of ammonia and subsequent alterations in glutamine synthesis, i.e. conditions associated with the pathophysiology of HE. Under physiological conditions, glutamine is fundamental for replenishment of the neurotransmitter pools of glutamate and GABA. The different isoforms of glutamine transporters play an important role in the transfer of this amino acid between astrocytes and neurons. A disturbance in the GABA biosynthetic pathways has been described in bile duct ligated (BDL) rats, a well characterized model of chronic HE. Considering that glutamine is important for GABA biosynthesis, altered glutamine transport and the subsequent glutamate/GABA-glutamine cycle efficacy might influence these pathways. Given this potential outcome, the aim of the present study was to investigate whether the expression of the glutamine transporters SAT1, SAT2, SN1 and SN2 would be affected in chronic HE. We verified that mRNA expression of the neuronal glutamine transporters SAT1 and SAT2 was found unaltered in the cerebral cortex of BDL rats. Similarly, no changes were found in the mRNA level for the astrocytic transporter SN1, whereas the gene expression of SN2 was increased by two-fold in animals with chronic HE. However, SN2 protein immuno-reactivity did not correspond with the increase in gene transcription since it remained unaltered. These data indicate that the expression of the glutamine transporter isoforms is unchanged during chronic HE, and thus likely not to participate in the pathological mechanisms related to the imbalance in the GABAergic neurotransmitter system observed in this neurologic condition.


ARTD1 regulates osteoclastogenesis and bone homeostasis by dampening NF-κB-dependent transcription of IL-1β.
While ADP-ribosyltransferase diphtheria toxin-like 1 (ARTD1, formerly PARP1) and its enzymatic activity have been shown to be important for reprogramming and differentiation of cells, such as during adipogenesis, their role and mechanism in regulating osteoclastogenesis and bone homeostasis are largely unknown. Here, in cell culture-based RANKL-induced osteoclastogenesis models, we show that silencing of ARTD1 or inhibition of its enzymatic activity enhances osteoclast differentiation and function. As a consequence of ARTD1 silencing or inhibition, the recruitment of p65/RelA to the IL-1β promoter, which is associated with transcriptionally active histone marks, IL-1β expression and inflammasome-dependent secretion of IL-1β are enhanced. This subsequently promotes sustained induction of the transcription factor Nfatc1/A and osteoclastogenesis in an autocrine manner via the IL-1 receptor. In vivo, Artd1-deficient mice display significantly decreased bone mass as a consequence of increased osteoclast differentiation. Accordingly, the expression of osteoclast markers is enhanced in mutant compared to wild-type mice. Together, these results indicate that ARTD1 controls osteoclast development and bone remodelling via its enzymatic activity by modulating the epigenetic marks surrounding the IL-1β promoter and expression of IL-1β and subsequently also Nfatc1/A.


What is the relationship between synaesthesia and visuo-spatial number forms?
This study compares the tendency for numerals to elicit spontaneous perceptions of colour or taste (synaesthesia) with the tendency to visualise numbers as occupying particular visuo-spatial configurations (number forms). The prevalence of number forms was found to be significantly higher in synaesthetes experiencing colour compared both to synaesthetes experiencing taste and to control participants lacking any synaesthetic experience. This suggests that the presence of synaesthetic colour sensations enhances the tendency to explicitly represent numbers in a visuo-spatial format although the two symptoms may nevertheless be logically independent (i.e. it is possible to have number forms without colour, and coloured numbers without forms). Number forms are equally common in men and women, unlike previous reports of synaesthesia that have suggested a strong female bias. Individuals who possess a number form are also likely to possess visuo-spatial forms for other ordinal sequences (e.g. days, months, letters) which suggests that it is the ordinal nature of numbers rather than numerical quantity that gives rise to this particular mode of representation. Finally, we also describe some consequences of number forms for performance in a number comparison task.